An estimated 190 million people worldwide carry the diagnosis of diabetes, making this disease one of the major threats to human health in the 21st Century. Currently, few natural animal models exist to evaluate molecular or cellular pathophysiology of this disease or to assess new preventive or therapeutic treatments. A general concept of both Type 1 and Type 2 diabetes is that a loss of beta ( ) cell mass occurs as a result of an inability to respond to changes in metabolic demand. Key molecular pathways involved in these responses are mostly unknown. By tissue-specific targeting of survivin, an inhibitor of apoptosis gene, we developed a novel genetic model for human diabetes. Animals developed diabetes, in a gene dosage-dependent fashion. All mice developed normally in utero, however at weaning age they became profoundly hyperglycemic, polyuric, and hyperlipidemic. Untreated mice uniformly died between 4 and 7 months of age from dehydration and hyperglycemic metabolic acidosis. Examination of the pancreas prior to weaning showed normal pancreatic architecture with normal islet cell size and insulin production. Following weaning, however, few, small islet cells remained and no beta ( ) cell could be detected. Thus, we believe our model offers novel biological insight into islet cell survival in the young animal and by extension, parallels the human course of insulin-dependent diabetes. The goals of this exploratory grant application are to more fully characterize this new genetic model at the molecular level. In Specific Aim 1, the role of the anti-apoptotic gene survivin in beta ( ) cell survival will be addressed by determining the molecular mechanisms of a decrease in beta ( ) cell mass that occur as a consequence of survivin loss. In Specific Aim 2, the hypothesis that dietary changes precipitate beta ( ) cell loss in the setting of this model will be tested. This pilot project has the potential to contribute novel insights into islet cell biology, to identify novel genetic pathways leading to the development of human diabetes, and to provide the foundation for future therapeutic studies of this disorder. Concurrent with the obesity epidemic, the incidence of diabetes is dramatically increasing every year. Complications of diabetes are a major contribution to US health-care costs and morbidity. Few natural animal models of diabetes exist to study disease progression or to develop new therapeutic strategies. This grant proposal introduces a novel genetic model of diabetes through which to study the biology of disease and the targeting of novel molecular agents for its treatment.